Discordant phenotypes and varying incidences of complex diseases in monozygotic twins as well as genetically identical organisms have long been attributed to differential environmental exposures. Accumulating evidence indicates, however, that epigenetic gene dysregulation by DNA methylation and histone modifications from environmental exposures also play a role in this differential susceptibility to disease. Thus, the overarching hypothesis of this grant application is that early exposure to environmental agents influences adult disease susceptibility by causing stable alterations in critical DNA control elements that regulate metastable epialleles - genes whose epigenome is established probabilistically during development, leading to variable gene expressivity and widely varying individual adult phenotypes. Despite a growing consensus on the importance of epigenetics in the etiology of chronic human diseases, the genes most prone to epigenetic dysregulation are incompletely defined. Moreover, neither the environmental agents most strongly affecting the epigenome nor the critical windows of vulnerability to environmentally induced epigenetic alterations have been characterized. These major deficits in knowledge have severely constrained our ability to systematically define and characterize the metastable epialleles mechanistically involved in the etiology of human diseases. The overall objective of this grant application is to help correct these deficiencies by using the viable yellow Agouti (Avy) mouse model, as well as human samples to identify environmentally responsive, metastable epialleles in the mouse and human genomes. Specifically, the intent is to determine if maternal dietary supplementation of Avy mice with low levels of the plasticizer bisphenol A (BPA) affects adult phenotype of the offspring by altering the fetal epigenome. Gene expression and genome-wide bioinformatic approaches to identify imprinted and non-imprinted metastable epialleles in both mice and humans will be employed. The results of this study should ultimately allow for improved diagnosis, treatment, and prevention of chronic human diseases such as asthma, diabetes, cancer, obesity and neurological disorders by targeting the epigenome rather than the genome. They will also be helpful in determining under what circumstances the mouse is an appropriate toxicological model for assessing human risk from agents that elicit their biological effect primarily by altering the epigenome.